Ageing Flashcards
What is longevity?
The length of the lifespan independent of the biological aging process.
Two individuals with the same lifespan are unlikely to experience the progression of aging at the same rate.
What are the differences between the evolution of longevity and ageing?
Longevity may have evolved to maximise opportunities to reproduce
Ageing may be a more random process arising from the impact of events over the life course.
What are the physiological changes in age?
Reduced epithelial barrier function
Reduction in brain volume/mass
Reduction in bone marrow volume
Decreased lung capacity
Decreased cardiac output and increased blood pressure
What are the pathological changes in age?
Increased incidence of cancer
Increased incidence of coronary heart disease
Increased incidence of obstructive lung diseases and asthma
Increased incidence of rheumatoid disorders
What are the psychological changes in age?
Altered sleep patterns
Cognitive decline
Memory impairment (recall and formation of new memories)
Reduced speech and rate of speech
Increased risk of depression
What is the Weissman theory of ageing?
An evolutionary basis for aging, based on the idea that aging may have evolved to benefit the species rather than the individual, by removing older members of a population to reduce competition for resources with younger members.
What is the accumulated mutation theory?
Progressive accumulation of DNA damage and mutation of genes encoding DNA repair enzymes
Most organisms (in the wild) die before reaching old age, so little benefit to the number of offspring (reproductive fitness) by living beyond reproductive years
Therefore – natural selection will act on harmful mutations early in life, but have power to select out the accumulation of mutations that are detrimental in older organisms
What is the antagonistic pleiotropy?
Some genes have more than one unconnected role or effect (pleiotropy)
Genes that promote a beneficial effect early in age (and boost number of offspring) but have negative effects in old age will be selected for by evolution
What is the disposalble soma theory?
Organisms have limited resources, and must balance these between investing in reproduction and maintaining and repairing the body
Resources spent early in live promoting development and reproduction are ‘lost’ to old age and can’t be used to support repair
What are program theories?
Program theories of aging suggest that aging follows a biological timetable
This might be a continuation of the growth and development programmes of fetal life and childhood
What is the programmed longevity theory?
Aging arises due to time-dependent changes in expression of key genes involved in growth or development
What is the immunological theory?
Progressive loss of immune system activity with increasing age leads to cellular stress and eventual death from impact of disease
What is the endocrine theory?
Hormonal influences (eg GH-IGFI) constitute a biological clock that determines the rate of aging of an organism
What are damage theories?
Organisms experience environmental assaults throughout their lifespan
These can arise from external insults (eg UV), or from intrinsic physiological processes (eg ROS)
Damage theories postulate that the cumulative impact of these assaults causes aging
What is the wear and tear theory?
Components of cells and tissues eventually wear out, leading to the aging of the organism
What is the cross-linking theory?
Accumulation of cross-linked proteins impairs cellular function, slowing down bodily processes and leading to aging
What is the rate of living theory?
An organisms rate of basal metabolism determines its lifespan
What is the Free-Radical Theory?
Reactive oxygen species (ROS) cause damage to cellular macromolecules, (DNA, proteins) and organelles, impairing function
What is the Somatic DNA damage theory?
Mutations are acquired faster than they can be repaired, so accumulate over time leading to a breakdown of genetic integrity
What criteria does a hallmark of ageing need to fulfil?
It should manifest during normal aging;
Its experimental aggravation should accelerate aging; and
Its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan
What are the hallmarks of ageing?
Genomic instability
Telomere attrition
Epigenetic alterations
Impaired proteostasis
Deregulated nutrient sensing
Mitochondrial dysfunction
Stem cell exhaustion
Cellular senescence
Altered intercellular communication
What causes genomic instability?
This damage arises from exposure to external sources (eg UV radiation) or body processes (eg free radicals)
Changes in DNA copy number and chromosome stability are observed with increasing age
What are some syndromes that affect genomic instability?
Some premature aging syndromes (Werner, Blooms) arise from mutations in DNA repair enzymes – indicating a link between aging and genetic integrity
What is telomere attrition?
The ends of chromosomes contain repeated DNA sequences known as telomeres
In most cells, telomeres cannot be replicated fully by the DNA replication machinery, so shorten with each round of cell division
What is genomic instability?
DNA damage is accumulated throughout life
As well as damage to nuclear DNA, there is also mitochondrial DNA damage, and changes to nuclear architecture (how the DNA is arranged and packaged within the nucleus) with advancing age
How does telomere attrition affect ageing?
Once the telomere reaches a critical shortness, cells enter senescence
Some cells (mostly stem cells) express an enzyme called telomerase, which can maintain telomere length
What epigenetic alterations affect ageing
Loss of DNA methylation, age-specific patterns of histone modification, and changes in the expression of enzymes that regulate DNA packaging and chromatin remodelling
What is proteostasis?
Controls the normal folding and maintenance of proteins in their folded state through chaperone (heat shock protein) activity).
Unfolded proteins are normally targeted for autophagy, or breakdown by the proteosome.
How does impaired proteostasis affect ageing?
Persistence of unfolded proteins leads to their aggregation, a situation associated with numerous age-related disorders (eg Alzheimers, Parkinsons)
How does deregulated nutrient sensing affect ageing?
Mutations that impair the function of the activity of the Growth Hormone (GH) – Insulin-Like Growth Factor I (IGFI) pathway are associated with increased lifespan and healthy aging
mTOR regulates many aspects of cell metabolism, and contributes
What is the function of AMPK?
Activated by low energy states, and promotes healthy aging by inhibiting mTOR
How does blocking nutrient sensing work?
Very low levels of GH-IGFI are incompatible with life, so it’s not possible to block this pathway completely to inhibit aging
Dietary (caloric) restriction is thought to work through this pathway
What are mitochondrial defects closely associated with?
Ageing and longevity
Age-related mitochondrial dysfunction leads to increased reactive oxygen species (ROS) which can damage cellular macromolecules
What are the mechanisms of mitochondrial dysfunction?
There is a loss of efficacy of the respiratory train with increasing age»_space; less energy for cellular processes
Accumulation of mtDNA mutations may lead to reduced bioenergetics, contributing to a decrease in cellular processes and aging
Mitochondria may become permeabilized (‘leaky’) with age, triggering apoptosis and inflammation
How does stem cell exhaustion affect ageing?
Cell cycle activity in aged stem cells is reduced»_space; divide less frequently
Loss of haematopoietic stem cell activity leads to reduced production of adaptive immune cells, and contributes to anaemia and myeloid cancers
What is senescence?
The stable arrest of the cell cycle
How does stem cell exhaustion occur?
May occur due accumulation of DNA damage and telomere shortening
What causes senescence?
This occurs in response to DNA damage, and prevents the ongoing proliferation of these dysfunctional cells.
These cells are efficiently removed by the immune system, preventing progression to cancer or aging
Removed cells are replaced by stem cell activity
How does senescence affect ageing?
In older cells, senescence still occurs, but stem cell activity is less efficient, so removed cells do not get replaced as effectively
The demand for replacement cells may increase, thus exhausting the capacity of the stem cells
Senescent cells also secrete pro-inflammatory cytokines, which may contribute to aging
Which intercellular signalling pathways become altered?
Age-related changes in inflammation, hormonal changes, and reduced immune system activity, along with resultant changes in microbiome
How do senescent cells influence other cells?
Senescent cells can influence those around them to enter senescence too (so called bystander effect) through communication to neighbouring cells via gap junctions
How could communication inhibit ageing?
Manipulation of signalling pathways, or prevention of chronic inflammation
What are the primary hallmarks of ageing?
Those which are the causes of damage which underpin aging
Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis
What are antagonistic hallmarks of ageing?
Those which are cell or tissue responses to the damage caused by primary hallmarks
Deregulated nutrient sensing
Mitochondrial dysfunction
Cellular senescence
What are integrative hallmarks of ageing?
Those which occur as a result of the above two categories
Stem cell exhaustion
Altered intercellular communication
